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1.
Thyroid ; 29(6): 809-823, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30924726

RESUMO

Background: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies, with no effective treatment currently available. The molecular mechanisms of ATC carcinogenesis remain poorly understood. The objective of this study was to investigate the mechanisms and functions of super-enhancer (SE)-driven oncogenic transcriptional addiction in the progression of ATC and identify new drug targets for ATC treatments. Methods: High-throughput chemical screening was performed to identify new drugs inhibiting ATC cell growth. Cell viability assay, colony formation analysis, cell-cycle analysis, and animal study were used to examine the effects of drug treatments on ATC progression. Chromatin immunoprecipitation sequencing was conducted to establish a SE landscape of ATC. Integrative analysis of RNA sequencing, chromatin immunoprecipitation sequencing, and CRISPR/Cas9-mediated gene editing was used to identify THZ1 target genes. Drug combination analysis was performed to assess drug synergy. Patient samples were analyzed to evaluate candidate biomarkers of prognosis in ATC. Results: THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), was identified as a potent anti-ATC compound by high-throughput chemical screening. ATC cells, but not papillary thyroid carcinoma cells, are exceptionally sensitive to CDK7 inhibition. An integrative analysis of both gene expression profiles and SE features revealed that the SE-mediated oncogenic transcriptional amplification mediates the vulnerability of ATC cells to THZ1 treatment. Combining this integrative analysis with functional assays led to the discovery of a number of novel cancer genes of ATC, including PPP1R15A, SMG9, and KLF2. Inhibition of PPP1R15A with Guanabenz or Sephin1 greatly suppresses ATC growth. Significantly, the expression level of PPP1R15A is correlated with CDK7 expression in ATC tissue samples. Elevated expression of PPP1R15A and CDK7 are both associated with poor clinical prognosis in ATC patients. Importantly, CDK7 or PPP1R15A inhibition sensitizes ATC cells to conventional chemotherapy. Conclusions: Taken together, these findings demonstrate transcriptional addiction in ATC pathobiology and identify CDK7 and PPP1R15A as potential biomarkers and therapeutic targets for ATC.

2.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 35(1): 145-150, 2018 02 25.
Artigo em Chinês | MEDLINE | ID: mdl-29745614

RESUMO

Tissue engineering has emerged as a promising approach for the repair and functional reconstruction of damaged tissues. The bionic and intelligentized scaffolds provide the structural support for cell growth and differentiation as well as tissue regeneration. The surface properties of the biological material implant, the nanotopology in particular, become key aspects in determining the success of the implant. Mesenchymal stem cells (MSC) are widely favored by researchers as the seed cells in tissue engineering. Recently, it has been shown that nanotopographical characteristics of biomaterials regulate a wide range of MSC properties from their cellular behavior and differentiation potential. Herein, this review will provide an update on studies investigating the roles of nanotopography in the development of tissue engineering using MSC.

3.
J Mol Med (Berl) ; 94(10): 1181-1194, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27339758

RESUMO

Keloid disease is characterized by hyperproliferation of responsive fibroblasts with vigorously continuous synthesis of extracellular matrix (ECM) components. Although the process by which keloids develop is poorly understood, most theories of the etiology are referred to fibroblast dysfunction. A central event in dermal repair is the release of growth factors in response to skin injury, which leads to the dysregulation of several crucial pathways that initiate the activation of keloid fibroblasts (KFs) and promote ECM accumulation. Hence, strategies aimed at reducing the production of these cytokines and/or disrupting their intracellular signal transduction have potential clinical significance for curing keloid. As the first oral multikinase inhibitor, sorafenib blocks a number of intracellular signaling pathways which are also pivotal for keloid pathogenesis. Therefore, evaluation of the effects of sorafenib on keloid disease seems timely and pertinent. In this study, we reported the identification of sorafenib that antagonized TGF-ß/Smad and MAPK/ERK signaling pathways in primary KFs. Impressively, treatment with sorafenib inhibited KF cell proliferation, migration, and invasion, and simultaneously reduced collagen production in KFs. Furthermore, we present ex vivo evidence that sorafenib induced the arrest of KF migration, the inhibition of angiogenesis, and the reduction of collagen accumulation. These preclinical observations suggest that sorafenib deserves systematic exploration as a candidate agent for the future treatment of keloids. KEY MESSAGE: The intracellular TGF-ß/Smad and MAPK/ERK signaling pathways is blocked by sorafenib. Sorafenib inhibits the proliferation, migration, invasion, and ECM deposition in keloid fibroblasts. Sorafenib reduces KF migration and concomitantly angiogenesis in keloid explants. Sorafenib is a promising agent for the treatment of keloids and hypertrophic scars.


Assuntos
Fibroblastos/efeitos dos fármacos , Queloide/metabolismo , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Niacinamida/análogos & derivados , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Smad/antagonistas & inibidores , Fator de Crescimento Transformador beta/antagonistas & inibidores , Adulto , Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Feminino , Fibroblastos/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Niacinamida/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sincalida/metabolismo , Proteínas Smad/metabolismo , Sorafenibe , Fator de Crescimento Transformador beta/metabolismo , Adulto Jovem
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